Hintergrund

Current gene therapy is irreversible and does not allow controlled transgene expression in case of side effects. The invention is a pharmacologically controlled one-vector expression system of a therapeutic factor (i.e. GDNF) with zero background expression, based on mifepristone (Mfp)-Gene Switch system arranging two cassettes.

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Problemstellung

Gene therapy in its current configuration is irreversible and does not allow controlled transgene expression in case of side effects. Only few regulated vector systems are available. Popular Tet-operon based systems show undesired immunigenic problems. Two vector systems, originally developed for safety control, are unlikely to be approved for human gene therapy. Our innovation enables a pharmacologically controlled one-vector expression system of neurological factors.

Lösung

The technology is a pharmacologically controlled one-vector expression system of a therapeutic factor (i.e. GDNF) with zero background expression, based on mifepristone (Mfp)-Gene Switch system arranging two cassettes in tail-to-head configuration (EP3235516): (1) a first expression cassette directing the expression of a regulator protein under the control of a first promoter, wherein the regulator protein is activated in the presence of an activator molecule, and (2) a second expression cassette directing the expression of a molecule of interest (neurological factor), comprising a promoter region, and the expression of the molecule of interest is induced by binding of the activated regulator protein to the promoter region.

In vivo proof of an efficient gene therapy for Parkinson's Disease (PD) using astrocytes as hosts for localized neurotrophic factor delivery has been achieved. The expression is achieved by a viral vector with enhanced tissue spread. The studies showed that astrocyte expressed glial cell line-derived neurotrophic factor (GDNF) provides in vivo restoration of motor performance in a clinically relevant lesion paradigm (Molec Therap 2012, 20, 534-543).

An in vivo adeno-associated virus (AAV)-mediated, Mifepristone-regulated Gene Switch system for the transgene expression of glial cell line-derived neurotrohic factor (GDNF) in the rat brain/CNS has been achieved. However it showed considerable background expression in the non-induced state (Molec. Therap. 2013, 2, e106).

Studies demonstrates pre-clinically in a rat PD model that short-term induced expression of glial cell-line derived neurotrophic factor (GDNF) is sufficient to provide: (i) substantial protection of nigral dopaminergic neurons from degeneration, and (ii) restoration of dopamine supply and motor behaviour in the partial stratial 6-OHDA model of PD. Monthly application of the inducing drug Mfp was sufficient to maintain neuroprotective and neurorestorative GDNF levels. The system can be induced consecutively several times. Moreover, the pharmacologically controlled system shows in vivo that discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease (Neurobiol. Dis. 2014, 65, 35-42).

Vorteile

One-vector systems.

Human components.

Activator is a clinically approved small drug (Mfp).

Tested in the rat CNS.

Control through discontinuous administration of activator molecule (Mfp) to control induction of expression of the therapeutically active molecule (i.e. GDNF).